Adjuvant Chemoradiotherapy or Chemotherapy After D2 Gastrectomy in Gastric Cancer: A Randomized Clinical Trial.

Importance: Despite advances in D2 gastrectomy (ie, gastrectomy with D2 lymphadenectomy) and adjuvant chemotherapy, the value of adding postoperative radiotherapy (RT) to adjuvant chemotherapy after D2 gastrectomy remains a topic of ongoing debate. Objective: To assess whether the addition of RT to the S-1 plus oxaliplatin (SOX) chemotherapy regimen increases disease-free survival (DFS) in patients with T4 or node-positive gastric cancer after D2 gastrectomy. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted between December 1, 2012, and August 30, 2022, at 5 large tertiary hospitals in China. Eligible patients were aged 18 to 70 years with gastric adenocarcinoma who underwent R0 resection with D2 lymphadenectomy, had pathologic stage T4 or node-positive disease, and had no evidence of metastasis (M0). Intention-to-treat statistical analyses were conducted from January 14 to March 31, 2025. Interventions: Participants were assigned 1:1 to receive concurrent chemoradiotherapy (SOX RT) or chemotherapy alone (SOX). The SOX RT group received 1 cycle of induction SOX, followed by RT (50.4 Gy in 28 fractions) with concurrent S-1 (50 mg twice daily), and then 3 cycles of SOX. The SOX group received 6 cycles of SOX (S-1 30-40 mg/m2 twice daily on days 1-14; oxaliplatin 130 mg/m2 on day 1, every 3 weeks). Main Outcomes and Measures: The primary end point was 3-year DFS. Secondary end points included overall survival (OS) and adverse events. Results: A total of 620 patients were randomly assigned to the SOX group (n = 311) or SOX RT group (n = 309). Patients had a median (IQR) age of 55 (47-62) years and included 401 males (64.7%). Overall, 274 patients (44.2%) had T4 disease, and 590 (95.2%) had node-positive disease. In the primary analysis for the prespecified 3-year DFS end point, there was no evidence of a between-group difference in DFS (SOX RT vs SOX: HR, 0.98; 95% CI, 0.73-1.33). Similarly, there was no evidence of a between-group difference in OS (HR, 0.86; 95% CI, 0.60-1.23). The Kaplan-Meier-estimated 3-year DFS rates were 70.5% in the SOX RT group and 69.3% in the SOX group (log-rank P = .93), and the corresponding 3-year OS rates were 80.8% and 78.4%, respectively (log-rank P = .41). At 5 years, the DFS rates were 60.0% and 57.3% (log-rank P = .76) and the corresponding OS rates were 73.7% and 71.4% (log-rank P = .55) in the SOX RT and SOX groups, respectively. Treatment-related adverse events were similar between groups. Conclusions and Relevance: In this randomized clinical trial of patients with T4 or node-positive gastric cancer who underwent D2 gastrectomy, SOX RT did not significantly improve DFS or OS. Accordingly, among patients with D2-resected gastric cancer, the findings do not support routine addition of adjuvant chemoradiotherapy to chemotherapy. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR-TRC-12002919.